Inappropriate angiogenesis is the leading cause of blinding eye disease in the western world. In the anterior portion of the eye it contributes to such conditions as corneal graft rejection, neovascular glaucoma, and uveal melanoma. In the posterior eye, conditions such as macular degeneration, diabetic retinopathy, and retinopathy of prematurity all disrupt retinal structure as a result of vessel growth and leakage. For many of these conditions there are genetic differences which alter an individual's susceptibility to disease. We have discovered a significant (> 10-fold) difference in angiogenic responsiveness among inbred mouse strains. We have been working to identify the genetic differences responsible for this difference. We have determined that angiogenic responsiveness is controlled by many different quantitative trait loci (QTLs). In the most recent funding period, we have demonstrated that two additional traits correlate with angiogenic responsiveness. First, we determined that the levels of circulating EPCs and CECs are closely correlated with angiogenic responsiveness in a number of inbred mouse strains. Then we used a laser-induced model of choroidal neovascularization to demonstrate that not only was corneal angiogenic responsiveness correlated with choroidal neovascularization, but both traits are also controlled by some of the same loci. Finally, for two of our QTLs we identified the specific molecular alteration responsible for the difference in angiogenesis. In each of these two cases a pigment-controlling gene was responsible for the difference in corneal angiogenic responsiveness. We now propose to continue this work by combining a newly possible haplotype-based mapping technique with more traditional interval mapping based on recombinant inbred mouse strains. We anticipate that this combination will allow us to rapidly identify the molecular alterations responsible for several additional QTLs. We expect that this will result in the identification of additional, unexpected, angiogenesis regulatory pathways. As a result of the study design, these pathways are also likely to also exhibit polymorphism in humans. These studies will provide candidate genes for human studies and the possibility of providing prognostic information for ocular angiogenic diseases. Finally, the identification of novel angiogenesis regulatory pathways has the potential to support the development of novel angiogenesis modulatory therapeutics. As a result, these studies may improve both prognostic and therapeutic approaches to blinding eye disease.